This proposal seeks to extend the focus of studies conducted during the previous funding period which were concerned with neural mechanisms of cocaine reinforcement and acute cocaine withdrawal, to an investigation of the neurobiological basis of protracted cocaine withdrawal and relapse. The proposed studies will employ a multidisciplinary research strategy to identify enduring post-cocaine changes at the neurochemical, neuroendocrine, and molecular level and to relate these perturbations to changes in the vulnerability to relapse as measured by the reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-associated stimuli, and footshock stress. The overall hyposthesis is that a predictive relationship exists between the severity of neurobiologic changes and the susceptibility to relapse in one or both of these behavioral models. The proposed studies will focus on forebrain dopamine and serotonin transmission, stress systems including extrahypothalamic corticotropin-releasing factor (CRF) function and pituitary-adrenocortical hormones, as well as on intracellular signal transduction systems including the MAP- kinase pathway and other signal transduction intermediates. The overall experimental plan is to first identify abnormalities in the targeted neurobiological systems throughout a 4 month protracted withdrawal phase in rats with a history of cocaine self-administration that mimics human cocaine binge abuse (Specific Aim 1). The behavioral significance of these disturbances will then be established in Specific Aim 2 by examining whether these changes, or their remission over the course of protracted abstinence, are paralleled by changes in susceptibility to the response-reinstating actions of cocaine cues and stess. Specific Aim 2 will also seek to identify specific neurobiological systems that mediate the effects of cocaine cues and stress, and whether functional abnormalities in these systems observed in Specific Aim 1 alter their response cocaine cues and stress. The role in relapse of neurobiological systems identified in Specific Aims 1 and 2 will then be verified in Specific Aim 3 by testing whether appropriate pharmacological manipulations can inhibit cocaine-seeking behavior induced by cocaine cues and stress. By increasing understanding of the neurobiological basis of protracted abstinence and relapse, these studies will have direct implications for the development of pharmacotherapeutic strategies for treatment of cocaine dependence and prevention of relapse.